J. Org. Chem. 1981,46,3479-3483
3479
Synthesis of 3-Aryl-3-pyridylallylamines Related to Zimelidine via Palladium-Catalyzed Amination Jan-E. Backvall,* Ruth E. Nordberg, and Jan-E. Nystrom Department of Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden
Thomas Hogberg* and Bengt Ulff Department of CNS-Medicinal Chemistry, Astra Lakemedel AB, S-151 85 Sodertdlje, Sweden
Received January 27, 1981 Reaction of aryl pyridyl ketones 1 with vinylmagnesium bromide followed by acetylation of the products 2 with acetic anhydride/EbN and with 4-(dimethy1amino)pyridine (DMAP) as a catalyst gave acetates 3 in high yields. Treatment of acetates 3 with dimethylamine in the presence of a palladium catalyst produced a mixture of E and 2 isomers of 3-aryl-3-pyridylallylamines4.
Zimelidine ((z)-4d) is a new antidepressant agent which promises to offer clinical advantages over presently available drugs.' In contrast to tricyclic antidepressant drugs, it selectively inhibits the serotonin neuronal reuptake.2
Scheme I
I 2gBr
@:Hax k
Me2NCH2
z-u
Several methods for the synthesis of 4d and its analogues have been d e ~ c r i b e dand , ~ ~in one of these6p6the tertiary alcohol 2 is converted to the rearranged allylic chloride 5, which on subsequent amination affords amines 4 (Scheme I). An attractive method for the synthesis of compounds 4 would be the direct allylic amination of the l-aryl-lpyridylpropene. Unfortunately no effective reactions for allylic amination have yet been described, and only procedures that give allylic amides from olefins are k n ~ w n . ~ - ~ In principle, amination of 7r-allylpalladium complexes constitutes an oxidative allylic amination,lOJ1since the 7r-allyl complexes can be generated from the olefin by using stoichometric amounts of palladium.12 In the present paper we have studied the palladium-catalyzed amination13 of allylic acetates 3 to produce 4, a reaction that proceeds (1)Coppen, A,; Rama Rao, V. A.; Swade, C.; Wood, K. Psychopharmacology 1979,63,125,199. (2)(a) Ross, S.B.; Ogren, S. 0.;Renyi, A. L. Acta Pharmacol. Toricol. 1976,39,152.(b) Ross, S.B.; Renyi, A. L. Neuropharmacology 1977,16, 57 V I .
(3) (a) Berntason, P. B.; Carlsson, P. A. E.; Corrodi, H. R. Belgian Patent 781 105, 1972;US. Patent 3 928369, 1975. (b) Astra Pharmaceutical AB. British Patent 1561 286 1980. (4)Astra Lakemedel AB. British Patent 1530804, 1978. ( 5 ) (a)Bamberg, P.; Hardegger, E.; Vegh, L. J. S.International Patent Application (PTC) WO 79/00024,1979. (b) Hogberg, K.;Lindgren, J. E.; Hogberg, T.; Ulff, B. Acta Pharm. Suec. 1979,16, 299. (6)Hogberg, T.; Ulff, B.; Renyi, A. L.; Ross, S. B., manuscript submitted for publication. (7)Schonberger, N.; Krasze, G. Justus Liebigs Ann. Chem. 1975,1725. (8)(a) Sharpless, K.B.; Hori, T.; Truesdale, L. K.; Dietrich, C. 0. J. Am. Chem. SOC.1976,98, 269. (b) Sharpless, K.B.; Hori, T. J . Org. Chem. 1976,41,176. (9)Keck, G. E.;Yates, J. B. Tetrahedron Lett. 1979,4627. (10)Akermark, B.; Zetterberg, K. Tetrahedron Lett. 1975,3733. (11)(a) Akermark, B.; Backvall, J. E.; Lowenborg, A.; Zetterberg, K. J. Organomet. Chem. 1979,C33,166. (b) Stakem, F.G.; Heck, R. F. J. Org. Chem. 1980,45,3584. (12)Trost, B.M. Tetrahedron 1977,33,2615. (13)(a) Atkins, K.E.; Walker, W. E.; Manyik, R. M. Tetrahedron Lett. 1970,3821. (b) Takahashi, K.;Miyake, A.; Hata, G. Bull. Chem. SOC.Jpn. 1972,45,230.(c)Trost, B.M.; GenBt, J. P. J.Am. Chem. SOC. 1976,98,8516.
4
CH - CH-LI
CH - CH 2NMe 2 L
X= 3-pyridyl L-pyridyl 2-pyridyl
H L - F L - C I I - B r L-OMe 2-Br a g h
b
c
d
e
f
via wallylpalladium complexes.
Results and Discussion The general route for the preparation of allylic amines 4 is outlined in Scheme I. Treatment of the ketone 1 with vinylmagnesium bromide gave the allylic alcohol 2 in about 85% yield. Acetylation of 2 with 4-(dimethylamino)pyridine (DMAP)14as a catalyst proceeded smoothly at room t e m p e r a t ~ r e , and ' ~ in most cases almost a quantitative yield of 3 was obtained. Reaction of the acetate 3 with dimethylamine in the presence of palladium acetylacetonate (Pd(acac).J and bis(dipheny1phosphino)ethane (14)Hofle, G.;Steglich, W.; Vorbrtiggen, H. Angew. Chem. 1978,90, 602. (15)Acetylation without DMAP (Ac20/pyridine)required more vig orous conditions (110 "C, 24 h), giving a considerable amount of allylic rearrangement product and a moderate yield.
0022-3263/81/1946-3479$01.25/00 1981 American Chemical Society
3480 J. Org. Chem., Vol. 46, No. 17, 1981
Backvall et al.
Table I. Palladium-Catalyzed Dimethylamination of Allylic Acetates 3'
~~
reaction time, h
phosphine % ' yield of 4 b Z / E C ratio biphos 1 72 1.O:l C6HS 44 1.1:1 2 biphos P-FC6H, biphos p-ClC,H, 79 1.2:l 1.7 biphos 1.2:1 p-BrC, H, 2 87 1.2:1 4 75 p-BrC,H, PPh 3 PBu 48 1.2:l p-BrC6H, 80 100
